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Treatment of Chronic HCV Genotype 3Robert G. Gish MDStaff Physician, Stanford University Medical CenterSenior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, ArizonaClinical Professor of Medicine, University of Nevada, Las VegasMedical Director, Hepatitis B FoundationVice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR)Last Updated: May 14, 2014Hepatitis Web StudyHepatitis C OnlineHepatitisweb studyBackground and DefinitionsInitial Treatment and Retreatment of Prior RelapsersRetreatment of Prior NonrespondersIssues and ControversiesFuture TherapiesSummaryTreatment of Chronic HCV Genotype 3Hepatitisweb studyHepatitisweb studyBackground and DefinitionsTreatment of Chronic Hepatitis C: Genotype 3Hepatitisweb studyHepatitisweb studyTreatment of Chronic HCV Genotype 3BackgroundHCV infects ~ 5 million people in the US todayGenotype 3 is the third most common HCV genotype in USUp to 85% of patients have contraindications for interferon therapyMajor linkage to IVDA in epidemiological studiesInterferes with lipid metabolism in hepatocytes and linked with fatty liverSlightly higher risk of developing cirrhosisHCV Geno 3 is the new Geno 1 in terms of lower response rates

Hepatitisweb studyVirologic Responses with HCV TherapySustained Virologic Response at 12 Weeks Post Therapy (SVR12)Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post TreatmentUndetectableTreatmentPost Treatment12 WeeksEnd of TreatmentSVR12Hepatitisweb studyVirologic Responses with HCV TherapyRelapser and Nonresponder (Null and Partial)Different Types of Virologic Failure with HCV TherapyTreatmentRelapserPartial ResponderNull ResponderUndetectableNonresponderNonresponder Hepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Accessed May 12, 2014AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsCriteria for Interferon IneligibleInterferon Ineligible is defined as one or more of the following:Intolerance to interferonAutoimmune hepatitis and other autoimmune disordersHypersensitivity to peginterferon or any of its componentsDecompensated hepatic diseaseMajor uncontrolled depressive illnessA baseline neutrophil count below 1500/L, a baseline platelet count below 90,000/L or baseline hemoglobin below 10 g/dLA history of preexisting cardiac diseaseHepatitisweb studyTreatment-Nave and Prior RelapsersTreatment of Chronic Hepatitis C: Genotype 3Hepatitisweb studyHepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Therapy for Patients with Genotype 3 Chronic HCVPatients with GT 3 HCV: Initial Treatment & Retreatment of Relapsers*Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 24 weeksAlternative Therapy, Eligible for Interferon Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeksNot Recommended Peginterferon + Ribavirin x 24-48 weeks Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Any Regimen with Telaprevir, Boceprevir, or Simeprevir*Patients who experienced relapse after Peginterferon plus Ribavirin therapyHepatitisweb studyTreatment-Nave & Prior Relapsers with GT3 Chronic HCVKey Studies that Support Treatment RecommendationsSofosbuvir + Ribavirin- FISSION- POSITRON - VALENCESofosbuvir + Ribavirin + Peginterferon- PROTONSofosbuvir + Ribavirin or Sofosbuvir + Ribavirin + Peginterferon- ELECTRONHepatitisweb studySource: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.2436Week012N =243N =256SVR12SVR12Sofosbuvir + Ribavirin for Treatment-Nave HCV GT 2 or 3FISSION Trial: DesignPeginterferon + RBV (fixed-dose)Sofosbuvir + RBV (weight-based)Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 g once weeklyWeight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgFixed-dose Ribavirin (in 2 divided doses): 800 mg/dayHepatitisweb studySofosbuvir + Ribavirin for Treatment-Nave HCV GT 2 or 3FISSION Trial: ResultsSVR12 by GenotypeSource: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.RBV = Ribavirin; PEG = Peginterferon 68/7052/67102/183110/176170/253162/243Hepatitisweb study12Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.N =71Placebo12 weeksSofosbuvir + RBV12 weeksN =207SVR12Sofosbuvir + Ribavirin for HCV GT 2 or 3 (PEG not an option)POSITRON Trial: Design24Week012SVR12Drug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgHepatitisweb studySofosbuvir + Ribavirin for HCV GT 2,3 (PEG not an option)POSITRON: Results with Sofosbuvir + RibavirinSVR12 by HCV GenotypeSource: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.Placebo arm = 0% SVR12101/10960/98Hepatitisweb study14Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]2436Week012Sofosbuvir + Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3 VALENCE: Treatment ArmsSVR12Sofosbuvir + RBV(n = 73)SVR12Sofosbuvir + RBV(n = 250)GT 2GT 3Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgOriginal Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatmentNote: 85 patients enrolled in placebo armHepatitisweb studySofosbuvir + Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment-Nave GT 3 with 24 weeks All-Oral TherapySVR12 for Treatment-Nave GT 3Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print] Hepatitisweb study16Source: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.Sofosbuvir + Peginterferon + Ribavirin in Treatment-Naive Genotypes 1-3PROTON Trial: DesignWeek0N =14Drug DosingSofosbuvir (SOF): 400 mg once daily, except as designated in arm that received 200 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgPeginterferferon alfa-2a (PEG): 180 g once weekly72n = 4812SOF + PEG + RBVn = 2548GT 2, 3GT 1SOF (200 mg) + PEG + RBV+ RVRPEG + RBV24 - RVR PEG + RBVn = 47SOF (400 mg) + PEG + RBV+ RVRPEG + RBV - RVR PEG + RBVSOF + PEG + RBVn = 26Hepatitisweb study17Sofosbuvir + Ribavirin + Peginterferon in Treatment-Naive Genotypes 1-3PROTON Trial: ResultsSVR 24 by Genotype and Treatment RegimenSource: Lawitz E, et al. Lancet Infect Dis. 2013;13:401-8.41/4842/4715/2623/25Genotype 1Genotype 2 or 3Hepatitisweb study18Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44. Sofosbuvir and Ribavirin +/- Peginterferon in GT 1-3ELECTRON Trial (Arms 1-8): DesignSOF + RBV Week0N =14Drug DosingSofosbuvir (SOF): 400 mg once dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgPeginterferon alfa-2a (PEG): 180 g once weekly24n = 9n = 108SOF + RBV + PEG (week 1-4)12n = 10SOF + RBV + PEG (week 1-8)n = 11SOF + RBV + PEG SOFSOF + RBV + PEG SOF + RBVSOF + RBV SVR12n = 10n = 10n = 10n = 25SVR12SVR12SVR12SVR12SVR12SVR12SVR1220GT 1 NullGT 2,3Nave GT 1 Naive Hepatitisweb study19Sofosbuvir and Ribavirin +/- Peginterferon in GT 3ELECTRON: Subset AnalysisSVR 12 for Treatment-Nave Genotype 3*Source: Gane EJ, et al. N Engl J Med. 2013;368:34-44. 6/6Treatment-Nave Genotype 36/66/67/710/10*Data for sofosbuvir monotherapy not shownHepatitisweb study20Retreatment of Prior NonrespondersTreatment of Chronic Hepatitis C: Genotype 3Hepatitisweb studyHepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 3 Chronic HCVPatients with GT 3 HCV: Retreatment of Prior Nonresponders*Recommended Therapy Sofosbuvir + Ribavirin x 24 weeksAlternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeksNot Recommended Peginterferon + Ribavirin +/- [Boceprevir or Simeprevir or Telaprevir] Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent Treatment of Decompensated Cirrhosis with Peginterferon*Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapyHepatitisweb studyTreatment Experienced Nonresponders with GT3 Chronic HCVKey Studies that Support Treatment RecommendationsSofosbuvir + Ribavirin- FUSION- VALENCESofosbuvir + Ribavirin + Peginterferon- LONESTAR-2Hepatitisweb studySource: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.N =98Sofosbuvir + RBV16 weeksSofosbuvir + RBV12 weeksN =103SVR12Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Design24Week0122816SVR12PlaceboDrug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgHepatitisweb studySofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Results for GT3SVR12 for Treatment-Experienced GT3Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.SOF = Sofosbuvir; RBV = Ribavirin19/6439/6314/385/2625/4014/23Hepatitisweb study25Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]2436Week012Sofosbuvir + Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3 VALENCE: Treatment ArmsSVR12Sofosbuvir + RBV(n = 73)SVR12Sofosbuvir + RBV(n = 250)GT 2GT 3Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgOriginal Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatmentNote: 85 patients enrolled in placebo armHepatitisweb studySofosbuvir + Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment Experienced GT 3SVR12 for Treatment-Experienced GT 3Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]Hepatitisweb study27Source: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: Design24Week012Sofosbuvir + Peginterferon + RibavirinN = 47SVR12Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 g once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgGT 2 or 3Hepatitisweb studySofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: ResultsSVR12 in Treatment-Experienced by HCV GenotypeSource: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.42/4722/2320/24Hepatitisweb study29Issues and ControversiesTreatment of Chronic Hepatitis C: Genotype 3Hepatitisweb studyHepatitisweb studyIssues and ControversiesCost of TherapySofosbuvir + PEG + RBV higher SVR than all oral (LONESTAR data)- Treat selected Geno 3 patients with Sofosbuvir + PEG + RBV?- Wait for FDC Ledipasvir-Sofosbuvir + RBV with 100% SVR?When to Defer Therapy- Decisions on when to warehouse?(Non) Role of IL-28b TestingDegree of Liver Fibrosis- How to stage?Hepatitisweb studyHow is cost of therapy impacting treatment decisions?Hepatitisweb studyHepatitisweb studyHepatitis C Genotype 3Estimated Medication Costs for Treatment-Nave & Prior RelapsersPatients with GT 3 HCV: Initial Treatment & Retreatment of RelapsersRegimen and DurationRegimen CostRecommended Therapy Sofosbuvir + Ribavirin x 24 weeks$169,000Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks$97,000Hepatitisweb study33Hepatitis C Genotype 3Estimated Medication Costs for Retreatment of NonrespondersPatients with GT 3 HCV: Retreatment of NonrespondersRegimen and DurationRegimen CostRecommended Therapy Sofosbuvir + Ribavirin x 24 weeks$169,000Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks$97,000Hepatitisweb study34HCV Therapy for Genotype 3 Chronic HCVCost Analysis Based on Cost per SVRPatient CharacteristicsRegimen OptionsSVRCost per SVRNave, no cirrhosisSOF + RBV x 24 wks93%$194,624SOF + PEG + RBV x 12 wks??Nave, cirrhosisSOF + RBV x 24 wks92%$196,739Treatment experienced, no cirrhosisWait until.???SOF + RBV x 24 wks85%$212,941Treatment experienced, cirrhosis SOF + RBV x 24 wks60%$301,667SOF + PEG + RBV x 12 wks83%$126,915Source for Figure: Camilla Graham, MD, MPH. Beth Israel Deaconess Medical CenterData Sources: (1) Lawitz E, et al. NEJM 2013; 368:1878-87. (2) Jacobson I, et al. NEJM 2013; 368:1867-77. (3) Antiviral Drugs Advisory Committee Meeting, FDA and Gilead reviews, 10/25/2013. (4) Package Insert, Gilead.com 12/7/2013Hepatitisweb studyTreat now or defer therapy? Hepatitisweb studyHepatitisweb studyFactors Favoring Treat NowAdvanced Fibrosis (F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal vein- Esophageal varicesSynthetic dysfunctionSystemic disease- Cryoglobulinemia (+RhF)Highly motivated patients/symptomsPatients with Increased Mortality Risk- All cause- HCC riskHepatitisweb studyHow do you treat patient that failed Sofosbuvir + Ribavirin? Hepatitisweb studyHepatitisweb studySource: Esteban R, et al. 49th EASL; April 2014. Abstract 08.Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Study FeaturesRetreatment of Sofosbuvir + Ribavirin Failure: FeaturesDesign: Open-label, study for patients with GT 2 or 3 who had failure with sofosbuvir + ribavirin in FISSION, POSITRON, or FUSION trialSetting: Europe, United States, and CanadaEntry Criteria - N = 107 patients with chronic HCV- HCV genotype 2 (10%) or HCV genotype 3 (90%)- Previous relapse on sofosbuvir plus ribavirin- Patients with compensated cirrhosis allowed to enrollRegimens (patients offered 2 possible regimens)- Sofosbuvir + Ribavirin x 24 weeks- Sofosbuvir + Peginterferon + Ribavirin x 12 weeksPrimary End-Point: SVR12Hepatitisweb studySource: Esteban R, et al. 49th EASL; April 2014. Abstract 08.Retreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Study Design2436Week012N = 73N = 34SVR12SVR12Sofosbuvir + RBVSofosbuvir + PEG + RBVDrug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 g once weeklyWeight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgGT2 or GT3Hepatitisweb studyRetreatment of SOF + RBV Failure with SOF-Containing Regimens in GT 2 or 3Results, by Genotype SVR12 by Regimen and HCV GenotypeSource: Esteban R, et al. 49th EASL; April 2014. Abstract 08.4/41/220/2224/38Hepatitisweb studyFuture Treatment OptionsHepatitis C: Genotype 3Hepatitisweb studyHepatitisweb studyFuture Regimens for GT-3Ledipasvir + Sofosbuvir- Lepidasvir: NS5A replication inhibitor- Sofosbuvir: NS5B polymerase inhibitorDaclatasvir + Sofosbuvir?- Daclatasvir: NS5A replication inhibitor- Sofosbuvir: NS5B polymerase inhibitorABT-450/r-Ombitasvir +/- Ribavirin?- ABT-450/r: NS3 protease inhibitor with ritonavir boosting- Ombitasvir (formerly ABT-267): NS5A replication inhibitorHepatitisweb studySource: Gane EJ, et al. 49th EASL. 2014: Abstract O6.Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study DesignLDV-SOF + RBVSVR12Week0N =14Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kg24GT1Prior Sofobuvirn = 20n = 19GT1CTP Class B12n = 25LDV-SOF SVR12n = 26LDV-SOF + RBVSVR12Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin LDV-SOF SVR12GT3Treatment NaiveHepatitisweb study44Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3ELECTRON 2: Study DesignSVR 12, by GT and Treatment RegimenSource: Gane EJ, et al. 49th EASL. 2014: Abstract O6.LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin19/19SOF-ExperiencedTreatment Naive13/2016/2526/26CTP Class BHepatitisweb study45Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040 Design: Treatment-Nave 24 Week RxSOF 7 days, then DCV + SOFSVR12Week024N =14Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF): 400 mg once dailyRibavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75 kg or 1200 mg/day if 75 kg)Ribavirin (RBV): GT 2 or 3 (800 mg/day)36Rx NaveGT 2 / 3

n = 44n = 14n = 1612DCV + SOFn = 14DCV + SOF + RBVSVR12SVR12SOF 7 days, then DCV + SOFSVR12Rx NaveGT 1a/1b

n = 44n = 14n = 15DCV + SOFn = 15DCV + SOF + RBVSVR12SVR12Hepatitisweb studyDaclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040: Subset Analysis for Treatment-Nave GT 3SVR12 by GT 3, by Treatment RegimenSource: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin5/76/65/5Hepatitisweb studySummary Points for Treatment of Chronic HCV GT-3Treat now with Sofosbuvir + Ribavirin x 24 weeksConsider IFN-based Rx in select patient who can tolerate IFN to shorten therapy, save costs and have a nominally higher SVR rateStage patient for liver disease and systemic diseaseLook for signs of fatty liver and metabolic syndromeGT 3 may be the new GT 1 but high SVR rates can be seen in selected patientsHepatitisweb studyThis slide deck is from the University of Washingtons Hepatitis C Online and Hepatitis Web Study projects.

Hepatitis C Onlinewww.hepatitisc.uw.edu

Hepatitis Web Studyhttp://depts.washington.edu/hepstudy/

Funded by a grant from the Centers for Disease Control and Prevention. Hepatitisweb studyHepatitisweb study